Strategies to Improve Outcomes for triple negative Breast Cancer Patients involv

尽管靶向治疗的承诺，细胞毒性化疗仍然是治疗三联 阴性乳腺癌（TNBC）患者。由于TNBC的异质性， 选择患者进行各种治疗至关重要。我们最近发现了TNBC亚型， 分子驱动器和临床前模型，以开发有效的治疗方法。在此，我们建议 三个具体的目标，以测试以下相互关联的假设：在TNBC患者与管腔，雄激素 受体（AR）表达亚型，AR和PISK信号传导协同驱动肿瘤生长， 这些接受AR拮抗剂（比卡鲁胺）联合PISK通路抑制剂治疗的患者将是 有效的治疗。在其余90%的TNBC患者中，高频率的p5 S突变和PISK 其肿瘤中的信号通路改变将导致对遗传毒性剂的治疗脆弱性 顺铂与PISK抑制剂联合给药。 具体目的1：a）通过比卡鲁胺+泛PISK的临床获益率测量，评价疗效 抑制剂（GDC-0941）在患有AR+转移性TNBC的患者中的作用。B）评价疗效，通过 在患有AR-转移性TNBC的患者中顺铂+ GDC-0941相对于单独顺铂的总体响应率。 我们将确定一组基因组标记物是否可以预测对这些治疗药物的敏感性或耐药性。 试验方案。具体目标2：确定顺铂的固有和获得性耐药机制 和PISK抑制剂在TNBC环境中的作用。具体目的：开发经验证的TNBC临床生物标志物 分型和用于选择患者用于未来的临床试验或新的标准治疗。 在假设驱动的临床试验中，对来自患者的特征良好的肿瘤进行综合分析， 允许发现敏感性和耐药性的机制以及可用于治疗的生物标志物。 开发新的治疗方案和选择患者进行未来试验。 相关性（参见说明）; 这项拟议的研究将研究三阴性乳腺癌（TNBC）的新治疗方法 基于疾病的分子驱动因素。我们正在将我们的临床前发现转化为创新， 针对TNBC患者的靶向、亚型特异性临床试验。我们将发现新的生物标志物来预测 对已知疗法（顺铂和比卡鲁胺）和新疗法（PISK抑制剂）的应答和耐药性;后者 对许多癌症类型的治疗都有意义。

Despite the promise of targeted therapies, cytotoxic chemotherapy remains the mainstay of treatment for triple negative breast cancer (TNBC) patients. Due to the heterogeneity of TNBC, the identification of biomarkers is critical to select patients for various therapies. We recently identified TNBC subtypes with corresponding molecular drivers and preclinical models to develop effective therapeutic approaches. Herein, we propose three specific aims to test the following interrelated hypotheses: In TNBC patients with the luminal, androgen receptor (AR)-expressing subtype, AR and PISK signaling synergistically drive tumor growth, and treatment of these patients with an AR antagonist (bicalutamide) in combination with a PISK pathway inhibitor will be an effective therapy. In the remaining 90% of TNBC patients, the high frequency of p5S mutations and PISK signaling pathway alterations in their tumors will result in therapeutic vulnerability to the genotoxic agent cisplatin given in combination with a PISK inhibitor. Specific Aim 1: a) To evaluate the efficacy, as measured by clinical benefit rate of bicalutamide + the pan-PISK inhibitor (GDC-0941) in patients with AR+ metastatic TNBC. b) To evaluate the efficacy, as measured by overall response rate of cisplatin + GDC-0941 versus cisplatin alone in patients with AR- metastatic TNBC. We will determine if a set of genomic markers can predict sensitivity or resistance to these therapeutic regimens tested. Specific Aim 2: To determine mechanisms of inherent and acquired resistance to cisplatin and PISK inhibitors in the TNBC setting. Specific Aim S: To develop validated clinical biomarkers for TNBC subtyping and use in selection of patients for future clinical trials or new standard treatments. Comprehensive analysis of well-characterized tumors from patients on hypothesis-driven clinical trials will allow discovery of mechanisms of sensitivity and resistance as well as biomarkers that can be used in the development of new treatment regimens and selection of patients for future trials. RELEVANCE (See instructions); The proposed research will investigate new therapeutic approaches for triple negative breast cancer (TNBC) based on the molecular drivers of the disease. We are translating our preclinical findings to innovative, targeted, subtype-specific clinical trials for TNBC patients. We will discover new biomarkers to predict response and resistance to known (cisplatin and bicalutamide) and new therapies (PISK inhibitors); the latter has implications for use in many cancer types.